Harden: Over the years you have continued the twin study. What else have
you been able to learn from the twins?

Fauci: We have done a number of transplantations. We recently reported
a series of sixteen to eighteen transplants from well donors to their
HIV-infected twin brothers. First of all, the transplants have not been
dramatically successful, so two things were learned from that. We learned
that in order to be able to reconstitute immunity we have to suppress
virus replication adequately, because the virus will only re-infect the
transplanted cells or the transfused cells.

The other thing that we learned, and this is what we are very actively
working on now, is that we have a number of lines of evidence to indicate
that the microenvironment of the immune system is destroyed by HIV, not
just the CD4positive cells. We do not have a complete handle on this,
but it is the work that we will be doing in 1994 and thereafter. We know
it from our work with the lymph nodes, the thymus, and from the stroma
of the bone marrow. It is conceivable that, even if you destroy or block
all the virus in a person, or even if you try to re-infuse cells, you
will not be able adequately to reconstitute the immune system unless you
provide a proper microenvironment in which those cells can thrive. That
is why we are starting to think in terms of the kinds of therapy, either
with cytokines, or even replacing tissue, like thymus implants, that re-establish
the lymphoid system microenvironment.

You ask what did the bone marrow transplant studies tell us? They told
us, since they were unsuccessful, that we are probably dealing with two
things: one is a virus that is still replicating. We know from our lymph
node work that there is plenty of virus in the body and it is replicating,
even though it appears from looking at the blood that there is not much
virus around. That was one of the most important results to come out of
our recent studies on the lymph nodes. But also, in addition, it tells
us that there is destruction of the milieu that the immune system needs
to regenerate and re-establish itself.

Although the data were generally negative, that is, the bone marrow
transplantation did not work, I think this work provided extraordinary
insight for future experiments that we are conducting now and that I think
we will probably be conducting for the next five years.

Harden: Let me follow up on this point. I was fascinated by your recent
Dyer Lecture that seemed to take all the findings from the beginning and
pull them together into a picture of the pathogenesis of AIDS. As we have
been looking through a number of documents, we have come across the names
of people in your laboratory whose work contributed to this picture. I
thought perhaps you could tell us how your laboratory functioned and which
groups were working on which pieces of the problem.

Fauci: We had a number of individuals, who were predominantly fellows,
who were in their training period. I assigned different tasks to each
of them, to work in a particular area. I tried to cover, as best as I
could, the salient areas that I felt would be important from an immunopathogenic
standpoint, because the underlying theme of the laboratory was the immunopathogenic
mechanisms of HIV infection.

We had the original work that I have mentioned with Cliff Lane looking
at hyperactivity of the immune system and at some of the selective T-cell
defects. But then Cliff made a major switch in commitment to doing clinical
investigations and clinical trials. He still maintained his interest in
basic science, but he has provided an invaluable component to the laboratory
now by translating what we do in the laboratory into clinical trials,
both immunological reconstitution as well as the antiretroviral work.

At that time Tom Folks was in the laboratory. He had been working formerly
as a fellow with [Dr.] Ken [Kenneth] Sell, and when Ken left, he joined
me in my laboratory. Tom and I had a very productive interaction in the
laboratory where we were involved in establishing permanent HIV-infected
cell lines and beginning the work on looking at the role of cytokines
in HIV infection.

Tom left and went to the CDC
[Centers for Disease Control and Prevention], but in the few years that
Tom was with me we collaborated well. There was also an Italian named
[Dr.] Guido Poli, who had come from Milan as a postdoctoral fellow. He
worked with Tom and me for a year or two. Then, when Tom left, Guido blossomed
as the main player in the cytokine work. He has been very productive in
delineating the role of TNF [tumor necrosis factor], GM-CSF [granulocyte-macrophage
colony-stimulating factor], IL-6 [interleukin 6], IL-1 [interleukin-1],
interferon gamma, interferon alpha, and other cytokines in the regulation
of HIV expression. In addition, he studied the autocrine and paracrine
loop of cytokine regulation of HIV. He continues to do that to this day.
He has been with us now for several years and unfortunately, he will be
leaving us to return to Italy soon.

In addition, we had [Dr.] Scott
Koenig, who, again as a fellow was interested more in how the body responds
to HIV. He did very important work, I think, in delineating the role of
cytolytic T cells in clearing HIV. He stayed at NIH for a few years, made
some important contributions, and then moved on to MedImmune Corporation.

At the time that Scott was here–I try to stagger my fellows by
bringing in new people as others get more senior and leave–a young
man from Italy named [Dr.] Giuseppe [Gepi] Pantaleo came into the laboratory.
Gepi Pantaleo has been one of the most impressive researchers in the laboratory.
He started off as a young fellow and now is making major contributions.
At first his area was looking at the cytolytic cells, taking over from
Scott Koenig, but then we got very interested in the role of viral burden
and replication in the lymph nodes. He is now focused predominantly on
that, and he and [Dr.] Cecilia Graziosi are working together on it in
the laboratory. So the laboratory has the Guido Poli mini-group that is
interested predominantly in the cytokines. It has the mini-group of Gepi
Pantaleo and Cecilia Graziosi working on the viral burden in lymph nodes
and on viral replication.

Then we had another smaller
group that was interested in precursor cells. That was work that was started
when [Dr.] Steven Schnittman was a fellow in the laboratory. Steve demonstrated,
for the first time that thymocytes, in vitro, even the thymocytes
that were not expressing CD4 molecules grossly but were so called “triple
negative” cells, were infectable by HIV. He published a very important
paper on that, and he also did some of the viral burden work in the peripheral
blood. Steve did this work in my laboratory at the time he was getting
ready to leave and go to the extramural program. [Dr.] Sharilyn Stanley
took over this work when Steve left. Now she is leading that mini-group
looking at the effect of HIV on the thymus, the thymic microenvironment,
and the bone marrow, and looking at the effect on precursor cells. Hers
is another mini-group that is also doing very important work in that regard.

Then we brought in [Dr.] Andy
[Andrew] Dayton, who is working with a group on looking at control of
viral gene expression, particularly the rev axis; so we have
a molecular virological approach there.

We also have people who are much more senior and independent who are
not predominantly working on AIDS, but who do HIV-related work. [Dr.]
Uli Siedenlist, who has been very much involved in cloning and describing
the role of the NF-kappa-B transcription activating factor, is fundamentally
a molecular biologist. He is now using that expertise to look at how HIV
uses the NF-kappa-B access for virus expression and how cytokines use
the NF-kappa-B access to induce HIV. Finally, [Dr.] John Kehl is another
former fellow of mine who is now a senior independent scientist. He has
trained [Dr.] Peter Ruckmann, a fellow from Germany, to perform some very
interesting work on the role of B-cell derived cytokines in the induction
of HIV expression.

All of these lines of research are now, I think, synergizing in the laboratory.
When a critical mass is created, then all of sudden you can look at the
big picture, at everything. You have the cytokine look, the precursor
look, the viral burden and lymph node look, the molecular virology look,
and the clinical immunological reconstitution look. All of those things
create an atmosphere in the laboratory that is perfectly suited for producing
the results you heard at the Dyer lecture. I was able to get up and talk
about the whole spectrum of HIV pathogenesis. People feed and nourish
each other. It is good when there is a critical mass of people all interested
in the same general theme, HIV, and how it destroys the body's immune
system, with each person investigating it from a slightly different perspective.

Harden: You
are in the position of doing basic research, of being very intimately
linked to work on AIDS, and, at the same time, you are in the public spotlight
as a chief spokesperson for AIDS. Beginning with Peter Duesberg, and most
recently in Robert Root Bernstein's book Rethinking AIDS, the
question has been raised, “Maybe HIV is not the cause of AIDS?"
Perhaps you would comment on the value of rethinking AIDS. How many times
do we rethink it?

Fauci: I do not think it is a question of totally rethinking AIDS. I
think it is a question of keeping an open mind about the mechanisms whereby
the virus destroys the body's immune system. There is no question that
the primary component of AIDS is the virus. Since there were not complete,
precise explanations available of how the virus destroys the body's immune
system, some people made an inappropriate leap. They said each and every
pathogenic event could not be explained on the basis of the virus killing
a cell, because it was perceived that there was not enough virus around
or there were other phenomena going on. Then, in a sense, they threw the
baby out with the bath water. They said that the virus had nothing to
do with it. It was just behavior. People were taking drugs, and people
were leading “promiscuous” sexual lives. Behavior itself was
causing AIDS.

The epidemiology, in and of itself, completely destroys that argument.
But rather than take a very strict unidimensional view, what we do–in
my laboratory–is realize that we do not have the complete explanation
of how the body's immune system is destroyed. We work on that. We know
that without the virus, there is no disease. But if you have the virus,
how do you get the disease? Rather than arguing about whether the virus
is involved or not, we say, “There is no question the virus is involved;
but, how is it damaging the immune system?” That is what I tried
to get across in my Dyer lecture in the spring of 1993, and in my plenary
lecture in Berlin at the International AIDS Conference. I spoke about
the multifactorial, multiphasic components of the immunopathogenesis and
viral pathogenesis of AIDS and how that would give us insight into the
design of therapeutic strategies.

We can now look at a prototypical HIV-infected individual and the different
phases of HIV disease. It is not the small window that we saw in 1981,
where a person would come in who was drastically ill, and the only thing
that we saw was someone who had no T4 cells and was very sick. But if
someone is watched from the beginning to the end of their illness, we
see that there are multifactorial components of HIV disease. There is
the virus itself, there is activation of the immune system. There are
other indirect mechanisms like inappropriate cell triggering, probably
apoptosis to a certain degree, cytokine secretion, regulation of HIV expression,
a disrupted microenvironment, and the profound immunosuppressed state.
These are all complex issues that need to be dissected out. We must keep
an open mind because everything cannot be explained by a single unidimensional
approach. Without the virus, nothing happens; however, the virus of itself
does not explain everything directly. That is the critical issue. That
is how I handle it when people say, “No, it is not the virus. Just
throw it out.”

It is interesting because there are many diseases whose pathogenesis
we do not understand, but nobody questions what causes those diseases.
For example, we do not have a very good idea of why people who have tuberculosis
get granuloma. Why does caseation occur? Why do we get cavitation? People
will say, wait a minute, sometimes if you look at the caseating lesion
in someone with tuberculosis you may not see very many microbes. Does
that mean that the tubercle bacillus is not responsible for the pathology?
No, the mechanisms are the induction of a variety of inflammatory and
necrotic processes. Just because each and every pathogenic event in AIDS
cannot be precisely explained is not a reason to say that HIV is not the
primary mover in AIDS.

Harden: Thank you. When you began your research, you did not know what
you were dealing with. How did you approach the biohazard problem? Were
you worried about your own safety, and your colleagues' safety?

Fauci: No. From the beginning we took the approach that we would be as
careful as we possibly could without being hysterical about it. There
was really no substantial fear. Maybe there should have been, but there
was not. Certainly there was no fear in taking care of patients. We had
been trained from the time we were in medical school that it is our responsibility
to take care of sick people. If someone does not want the responsibility
then he or she should go do something else. There was never a question
in my mind, or in Cliff Lane's mind, or in the minds of the people who
came after us, that this was what we had to do. We decided we wanted to
do it.